1. Technical Field
The present invention relates to compositions of antimicrobial agents. More particularly the invention relates to formulations of an antimicrobial agent which render the drug potent against organisms normally considered to be resistant to the agent.
2. Background of the Invention
Based upon in vitro microbicidal sensitivity tests, the level of an antimicrobial drug considered effective against a particular organism may be determined. This is referred to as the MIC (minimum inhibitory concentration) of the drug. On the other hand, safety studies will determine the amount of drug that can be safely given to a patient or test animal. This maximal amount of drug that can be dosed will determine the maximal biological exposure to the host animal, normally measured by the area under the curve (AUC) of the plot of drug concentration vs. time, the peak height of the plot of drug concentration vs. time, tissue levels vs. time, etc. The instantaneous tissue or plasma level of the in vivo experiment can be compared with the MIC value to determine relative efficacy of the attainable drug levels in the biological fluids. The actual comparison must be corrected for plasma protein binding, inasmuch as only the free drug level is the important parameter because it is in this state that the drug is freely diffusible to cross biological membranes.
As a result of such analysis, clinical literature has been established specifying what drugs can be used generally for certain strains of organisms, or more precisely, for certain strains of organisms with MIC values below certain levels. As an example, the antifungal agent itraconazole is not considered effective for strains of Candida albicans with MIC>8 for this drug (e.g., for C. albicans strain c43 (ATCC number 201794), MIC80=16 μg/ml for SPORANOX® itraconazole). These strains of Candida albicans are considered to be resistant to itraconazole. This presupposes the standard dosing level of this drug that can be administered.
However, if a method were available to substantially increase the amount of the antimicrobial drug (e.g., itraconazole) that could be administered, than it might be possible to treat infections hithertofore considered untreatable by this agent. Such a method is available through formulation of the drug as a nanosuspension. Submicron sized drug crystals stabilized by a surfactant coating have been found, in some cases, not to dissolve immediately upon injection into the blood stream. Instead, they are captured by fixed macrophages of the spleen and liver. From this sanctuary, the drug will be slowly released over a prolonged period of days. This is in contrast to conventionally solubilized drugs, which when injected, decrease in blood concentration at a much faster rate.
An example of an antimicrobial agent which is conventionally formulated to increase the solubility of the drug is the triazole antifungal agent itraconazole (FIG. 2). Itraconazole is effective against systemic mycoses, particularly aspergillosis and candidiasis. New oral and intravenous preparations of itraconazole have been prepared in order to overcome bioavailability problems associated with a lack of solubility. For example, the bioavailability of itraconazole is increased when it is formulated in hydroxypropyl-beta-cyclodextrin, a carrier oligosaccharide that forms an inclusion complex with the drug, thereby increasing its aqueous solubility. The commercial preparation is known by the tradename SPORANOX® Injection and was originated by JANSSEN PHARMACEUTICAL PRODUCTS, L.P. The drug is currently manufactured by Abbott Labs and distributed by Ortho Biotech, Inc.
Intravenous itraconazole may be useful in selected clinical situations. Examples are achlorhydria in AIDS patients, an inability to effectively absorb oral medications due to concurrent treatments with other drugs, or in critical-care patients who cannot take oral medications. The current commercial product, SPORANOX® Injection, is made available in 25 mL glass vials that contain 250 mg of itraconazole, with 10 g of hydroxypropyl-beta-cyclodextrin (referenced as “HPBCD”). These vials are diluted prior to use in 50 mL of 0.9% saline. The resulting cyclodextrin concentration exceeds 10% (w/v) in the reconstituted product. Although HPBCD has been traditionally regarded as safe for injection, high concentrations, such as 10%, have been reported in animal models to induce significant changes to endothelial tissues (Duncker G.; Reichelt J., Effects of the pharmaceutical cosolvent hydroxypropyl-beta-cyclodextrin on porcine corneal endothelium. (Graefe's Archive for Clinical and Experimental Opthalmology (Germany) 1998, 236/5, 380-389).
Other excipients are often used to formulate poorly water-soluble drugs for intravenous injection. For example, paclitaxel (Taxol®, produced by Bristol-Myers Squibb) contains 52.7% (w/v) of Cremophor® EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. Administration of Cremophor® EL can lead to undesired hypersensitivity reactions (Volcheck, G. W., Van Dellen, R. G. Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and review. Annals of Allergy, Asthma, and Immunology, 1998, 80, 159-163; Singla A. K.; Garg A.; Aggarwal D., Paclitaxel and its formulations. International Journal of Pharmaceutics, 2002, 235/1-2, 179-192).
The present invention discloses a composition which renders antimicrobial drugs more effective on the basis of their physical and biological properties than in their unformulated state or in their existing formulations. The approach used is to formulate the antimicrobial agents as nanosupensions. This permits using of the improved formulation to treat microbes conventionally thought to be resistant to the unformulated drug. Conventional formulation approaches attempt to enhance solubility or bioavailability only. Such methods include pH change, modification of the salt form, use of organic modifiers, or cyclodextrin. The approach disclosed in the present invention involves altering the pharmacokinetic characteristic of the drug, permitting far greater dosing, resulting in improved efficacy over and above what can be accomplished by improving solubility and bioavailability only. Acute toxicity tests have demonstrated that much more drug, when formulated as a nanosuspension, can be administered to animals. More of the drug is therefore available at the target organ to exert efficacy.